Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-15
2002-05-28
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S265800, C514S338000, C514S406000
Reexamination Certificate
active
06395905
ABSTRACT:
BACKGROUND
SUMMARY OF THE INVENTION
The present invention is directed to 4-oxo-tetrahydroindozole-3-carboxamide compounds according to Formula (I) or a pharmaceutically acceptable salt thereof that are GABA-A Alpha 5 ligands useful for enhancing cognition:
The,present invention relates to tetrahydroindazole derivatives, pharmaceutical compositions comprising them and to their use in therapy. More particularly, this invention is concerned with substituted derivatives which are ligands for GABA
A
receptors, in particular for GABA
A
&agr;5 receptors and are therefore useful in therapy particularly where cognition enhancement is required.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA
A
receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABA
B
receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABA
A
receptor subunits were cloned the number of known members of the mammalian family has grown to thirteen (six &agr; subunits, three &bgr; subunits, three &ggr; subunits and one &dgr; subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993.
Although knowledge of the diversity of the GABA
A
receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an &agr; subunit, a &bgr; subunit and a &ggr; subunit constitute the minimum requirement for forming a fully functional GABA
A
receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a &dgr; subunit also exists, but is apparently uncommon in the native receptor.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABA
A
receptor exists in pentameric form. The selection of at least one &agr;, one &bgr; and one &ggr; subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit. combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include &agr;1&bgr;2&ggr;2, &agr;2&bgr;2/3&ggr;2, &agr;3&bgr;&ggr;2/3, &agr;2&bgr;&ggr;1, &agr;5&bgr;3&ggr;2/3, &agr;6&bgr;&ggr;2, &agr;6&bgr;&dgr; and &agr;4&bgr;&dgr;. Subtype assemblies containing an &agr;1 subunit are present in most areas of the brain and account for over 40% of GABA
A
receptors in the rat. Subtype assemblies containing &agr;2 and &agr;3 subunits respectively account for about 25% and 17% of GABA
A
receptors in the rat. Subtype assemblies containing an &agr;5 subunit are primarily hippocampal and represent about 4% of receptors in the rat.
A characteristic property of some GABA
A
receptors is the presence of a number of modulatory sites, of which the most explored is the benzodiazepine (BZ) binding site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABA
A
receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABA
A
receptor comprising the &agr;1 subunit in combination with &bgr;2 and &ggr;2. This is the most abundant GABA
A
receptor subtype, representing almost half of all GABA
A
receptors in the brain.
Two other major populations are the &agr;2&bgr;&ggr;2 and &agr;3&bgr;&ggr;2/3 subtypes. Together these constitute approximately a further 35% of the total GABA
A
receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain &agr;5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at &agr;1&bgr;&ggr;2, &agr;2&bgr;&ggr;2 or &agr;3&bgr;&ggr;2 subunits will possess desirable anxiolytic properties. The &agr;1-selective GABA
A
receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ
1
binding site is mediated through GABA
A
receptors containing the al subunit. Accordingly, it is considered that GABA
A
receptor agonists which bind more effectively to the &agr;2 and/or &agr;3 subunit than to &agr;1 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at &agr;1 might be employed to reverse sedation or hypnosis caused by &agr;1 agonists.
A number of dementing illnesses such as Alzheimer's disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness. It is believed this can be done utilising compounds which are ligands for the GABA
A &agr;
5 receptor subtype.
SUMMARY OF THE INVENTION
The present invention is directed to 4-oxo-tetrahydroindozole-3-carboxamide compounds according to Formula (I) or a pharmaceutically acceptable salt thereof that are GABA-A Alpha 5 ligands useful for enhancing cognition:
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R
1
and R
4
are independently chosen from hydrogen, halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
haloalkyl, C
2-6
haloalkenyl and C
2-6
haloalkynyl:
R
2
is hydrogen or C
1-6
alkyl; and
Ar is phenyl, a 5-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms chosen from N, O and S, no more than one of which is O or S, or a 6-membered heterocyclic group containing one or two nitrogen atoms, each of which groups Ar is unsubstituted or substituted by from one to three groups independently chosen from halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
1-6
alkoxy, C
2-6
alkenyloxy, C
2-6
alkynyloxy, C
3-7
cycloalkoxy, C
1-6
haloalkyl, C
2-6
haloalkenyl, C
2-6
haloalkynyl, amino, C
1-6
alkylamino, di(C
1-6
)alkylamino, hydroxy, hydroxy C
1-6
alkyl, cyano, nitro, amino C
1-6
alkyl, C
1-6
alkylaminoC
1-6
alkyl, di(C
1-6
alkyl)aminoC
1-6
alkyl or C
1-6
alkoxycarbonylaminoC
1-6
alkyl.
R
1
is preferably hydrogen, halogen or C
1-6
alkyl and is particularly hydrogen.
R
2
is preferably hydrogen or methyl especially hydrogen.
R
4
is preferably hydrogen.
Ar is preferably phenyl or pyridine. When Ar is pyridine it may be 2-pyridine.
Ar is preferably unsubstituted or substituted with one or two groups independently selected from methyl, fluoro, chloro, methoxy, ethoxy, aminomethyl, aminoethyl, hydroxy, methylaminoethyl, dimethylaminoethyl and t-butoxycarbonylaminomethyl, especially from methoxy, fluoro, aminoethyl, methylaminoethyl, dimethylaminoethyl and t-butoxycarbonylaminomethyl.
Specific Examples of compounds according to the present invention are:
4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid phenylamide;
4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid-2,5-difluorophenylamide;
4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid pyridin-2-ylamide;
4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid 4-methoxyphenylamide; and
4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid 4-(2-aminoethyl)phenylamide; and the pharmaceutically acceptable salts thereof.
Further specific examples of compounds according to the present inve
Bryant Helen Jane
Chambers Mark Stuart
Merck Sharp & Dohme Ltd.
Saeed Kamal
Thies J. Eric
Winokur Melvin
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